Abstract：
Genetic variants of the OX40 ligand (OX40L) locus are associated with the risk of systemic lupus erythematosus (SLE), it is unclear how the OX40L blockade delays the lupus phenotype. Therefore, we examined the effects of an anti-OX40L antibody in MRL/Lpr mice. Next, we investigated the effect of anti-OX40L on immunosuppression in keyhole limpet hemocyanin-immunized C57BL/6J mice. In vitro treatment of anti-OX40L in CD4+ T and B220+ B cells was used to explore the role of OX40L in the pathogenesis of SLE. Anti-OX40L alleviated murine lupus nephritis, accompanied by decreased production of anti-dsDNA and proteinuria, as well as lower frequencies of splenic T helper (Th) 1 and T-follicular helper cells (Tfh). In keyhole limpet hemocyanin-immunized mice, decreased levels of immunoglobulins and plasmablasts were observed in the anti-OX40L group. Anti-OX40L reduced the number and area of germinal centers. Compared with the control IgG group, anti-OX40L downregulated CD4+ T-cell differentiation into Th1 and Tfh cells and upregulated CD4+ T-cell differentiation into regulatory T cells in vitro. Furthermore, anti-OX40L inhibited toll-like receptor 7-mediated differentiation of antibody-secreting cells and antibody production through the regulation of the SPIB-BLIMP1-XBP1 axis in B cells. These results suggest that OX40L is a promising therapeutic target for SLE.
摘要：
OX40配体（OX40L）基因座的遗传变异与系统性红斑狼疮（SLE）的风险相关，目前尚不清楚OX40L阻断是如何延迟狼疮表型的.因此,我们检查了抗OX40L抗体在MRL/Lpr小鼠中的作用。接下来,我们研究了抗OX40L对匙孔血蓝蛋白免疫C57BL/6J小鼠免疫抑制的影响。在CD4+T细胞和B220+B细胞中使用抗OX40L的体外治疗来探讨OX40L在SLE发病机制中的作用。抗OX40L缓解小鼠狼疮性肾炎，伴随着抗dsDNA和蛋白尿的产生减少，以及较低频率的脾辅助T（Th）1和T滤泡辅助细胞（Tfh）。在匙孔血蓝蛋白免疫的小鼠中，在抗OX40L组中观察到免疫球蛋白和成浆细胞水平降低。抗OX40L减少了生发中心的数量和面积。与对照IgG组相比，抗OX40L在体外下调CD4+T细胞分化为Th1和Tfh细胞，并上调CD4+T细胞分化为调节性T细胞。此外，抗OX40L通过调节B细胞中的SPIB-BLIMP1-XBP1轴抑制Toll样受体7介导的抗体分泌细胞分化和抗体产生。这些结果表明OX40L是SLE的有希望的治疗靶标。
